6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections.

Peripheral neuropathy [see Warnings and Precautions ( 5.1)]
Myelosuppression [see Warnings and Precautions ( 5.2)]
Hypersensitivity reactions [see Warnings and Precautions ( 5.4)]
Cardiac Adverse reactions [see Warnings and Precautions ( 5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

Unless otherwise specified, assessment of adverse reactions is based on one randomized study (Study 046) and one single-arm study (Study 081). In Study 046, 369 patients with metastatic breast cancer were treated with IXEMPRA 40 mg/m 2 administered intravenously over 3 hours every 21 days, combined with capecitabine 1000 mg/m 2 twice daily for 2 weeks followed by a 1-week rest period. Patients treated with capecitabine as a single agent (n=368) in this study received 1250 mg/m twice daily for 2 weeks every 21 days. In Study 081, 126 patients with metastatic or locally advanced breast cancer were treated with IXEMPRA 40 mg/m 2 administered intravenously over 3 hours every 3 weeks.

The most common adverse reactions (≥20%) reported by patients receiving IXEMPRA were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional reactions occurred in ≥20% in combination treatment: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation. The most common hematologic abnormalities (>40%) include neutropenia, leukopenia, anemia, and thrombocytopenia.

Table 4 presents nonhematologic adverse reactions reported in 5% or more of patients. Hematologic abnormalities are presented separately in Table 5.

Table 4 presents nonhematologic adverse reactions reported in 5% or more of patients. Hematologic abnormalities are presented separately in Table 5.

b A composite of multiple terms.
c Three patients (1 %) experienced Grade 5 (fatal) febrile neutropenia. Other neutropenia-related deaths (9) occurred in the absence of reported febrile neutropenia [see Warnings and Precautions ( 5.2)].
d No grade 4 reports.
e Peripheral sensory neuropathy was defined as the occurrence of any of the following: areflexia, burning sensation, dysesthesia, hyperesthesia, hypoesthesia, hyporeflexia, neuralgia, neuritis, neuropathy, neuropathy peripheral, neurotoxicity, painful response to normal stimuli, paresthesia, pallanesthesia, peripheral sensory neuropathy, polyneuropathy, polyneuropathy toxic and sensorimotor disorder. Peripheral motor neuropathy was defined as the occurrence of any of the following: multifocal motor neuropathy, neuromuscular toxicity, peripheral motor neuropathy, and peripheral sensorimotor neuropathy.
f Palmar-plantar erythrodysesthesia (hand-foot syndrome) was graded on a 1 -3 severity scale in Study 046.
			Study 046		Study 081
	IXEMPRA with capecitabine n=369		Capecitabine n=368		IXEMPRA Single Agent n=126
Adverse Reaction	All Grades	Grade 3/4	All Grades	Grade 3/4	All Grades	Grade 3/4
Preferred Term	(%)	(%)	(%)	(%)	(%)	(%)
Infections and Infestations
Upper respiratory tract infection	4	0	3	0	6	0
Blood and Lymphatic System Disorders				1 d		3 d
Febrile neutropenia	5	4 c	1	1 d	3	3 d
Immune System Disorders						1 d
Hypersensitivity b	2	1 d	0	0	5	1 d
Metabolism and Nutrition Disorders
Anorexia b	34	3 d	15	1 d	19	2 d
Dehydration b	5	2	2	<1 d	2	1 d
Psychiatric Disorders
Insomnia b	9	<1 d	2	0	5	0
Nervous System Disorders Peripheral neuropathy
Sensory neuropathy b	65	21	16	0	62	14
Motor neuropathy b	16	5 d	<1	0	10	1 d
Headache	8	<1 d	3	0	11	0
Taste disorder b	12	0	4	0	6	0
Dizziness	8	1 d	5	1 d	7	0
Eye Disorders
Lacrimation increased	5	0	4	<1 d	4	0
Vascular Disorders
Hot flush b	5	0	2	0	6	0
Respiratory, Thoracic, and Mediastinal Disorders
Dyspnea b	7	1	4	1	9	1 d
Cough b	6	0	2	0	2	0
Gastrointestinal Disorders
Nausea	53	3 d	40	2 d	42	2 d
Vomiting b	39	4 d	24	2	29	1 d
Stomatitis/mucositis b	31	4	20	3 d	29	6
Diarrhea b	44	6 d	39	9	22	1 d
Constipation	22	0	6	<1 d	16	2 d
Abdominal pain b	24	2 d	14	1 d	13	2 d
Gastroesophageal reflux disease b	7	1 d	8	0	6	0
Skin and Subcutaneous Tissue Disorders
Alopecia b	31	0	3	0	48	0
Skin rash b	17	1 d	7	0	9	2 d
Nail disorder b	24	2 d	10	<1 d	9	0
Palmar-plantar erythrodysesthesia syndrome b	64	18 d	63	17 d	8	2 d
Pruritus	5	0	2	0	6	1 d
Skin exfoliation b	5	<1 d	3	0	2	0
Skin hyperpigmentation b	11	0	14	0	2	0
Musculoskeletal, Connective Tissue, and Bone Disorders
Myalgia/arthralgia b	39	8 d	5	<1 d	49	8 d
Musculoskeletal pain b	23	2 d	5	0	20	3 d
General Disorders and Administration Site Conditions
Fatigue/asthenia b	60	16	29	4	56	13
Edema b	8	0	5	<1 d	9	1 d
Pyrexia	10	1 d	4	0	8	1 d
Pain b	9	1 d	2	0	8	3 d
Chest pain b	4	1 d	<1	0	5	1 d
Investigations
Weight decreased	11	0	3	0	6	0

Table 5: Hematologic Abnormalities in Patients with Metastatic or Locally Advanced Breast Cancer Treated with IXEMPRA
aG-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte macrophage colony stimulating factor) was used in 20% and 17% of patients who received IXEMPRA in Study 046 and Study 081, respectively.
	Study 046				Study 081
	IXEMPRA with capecitabine n=369		Capecitabine n=368		IXEMPRA single agent n=126
Hematology Parameter	Grade 3 (%)	Grade 4 (%)	Grade 3 (%)	Grade 4 (%)	Grade 3 (%)	Grade 4 (%)
Neutropenia a	32	36	9	2	31	23
Leukopenia (WBC)	41	16	5	1	36	13
Anemia (Hgb)	8	2	4	1	6	2
Thrombocytopenia	5	3	2	2	5	2

The following serious adverse reactions were also reported in 1323 patients treated with IXEMPRA as single agent or in combination with other therapies in clinical studies.

Infections and Infestations: sepsis, pneumonia, infection, neutropenic infection, urinary tract infection, bacterial infection, enterocolitis, laryngitis, lower respiratory tract infection

Blood and Lymphatic System Disorders: coagulopathy, lymphopenia

Metabolism and Nutrition Disorders: hyponatremia, metabolic acidosis, hypokalemia, hypovolemia

Nervous System Disorders: cognitive disorder, syncope, cerebral hemorrhage, abnormal coordination, lethargy

Cardiac Disorders: myocardial infarction, supraventricular arrhythmia, left ventricular dysfunction, angina pectoris, atrial flutter, cardiomyopathy, myocardial ischemia

Vascular Disorders: hypotension, thrombosis, embolism, hemorrhage, hypovolemic shock, vasculitis

Respiratory, Thoracic, and Mediastinal Disorders: pneumonitis, hypoxia, respiratory failure, acute pulmonary edema, dysphonia, pharyngolaryngeal pain

Gastrointestinal Disorders: ileus, colitis, impaired gastric emptying, esophagitis, dysphagia, gastritis, gastrointestinal hemorrhage

Hepatobiliary Disorders: acute hepatic failure, jaundice

Skin and Subcutaneous Tissue Disorders: erythema multiforme

Musculoskeletal, Connective Tissue, and Bone Disorders: muscular weakness, muscle spasms, trismus

Renal and Urinary Disorders: nephrolithiasis, renal failure

General Disorders and Administration Site Conditions: chills

Investigations: increased transaminases, increased blood alkaline phosphatase, increased gamma-glutamyltransferase

6.2 Postmarketing Experience

The following adverse reaction has been identified during postapproval use of IXEMPRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Procedural Complications: Radiation recall